3-aryl-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyramide and derivatives as antifungal agents

ABSTRACT

Compounds of the formula ##STR1## or a pharmaceutically or agriculturally acceptable acid addition salt thereof, wherein R is 5-chloro-2-pyridyl, or phenyl optionally substituted by one to three substituents, each independently selected from F, Cl, Br, I, CF 3 , C 1  -C 4  alkyl and C 1  -C 4  alkoxy; R 1  is CN, CSNH 2  or CONR 2  R 3  where either 
     (a) R 2  is H or certain alkyl groups and R 3  is H or certain alkyl, substituted alkyl, aralkyl, phenyl or cycloalkyl groups, or 
     (b) R 2  and R 3  taken together with the nitrogen atom to which they are attached form a nitrogen heterocyclic group, optionally containing an oxygen atom or NR 4  group, as a ring member and R 4  is H, C 1  -C 4  alkyl; C 2  -C 4  alkanoyl or (C 1  -C 4  alkoxy)carbonyl; 
     R 5  and R 6  are each H or CH 3  ; methods for their use in combatting fungal infections in plants, seeds and animals, including humans, pharmaceutical and agricultural compositions containing them and intermediates therefor.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of application Ser. No. 808,390, filedNov. 29, 1985, now abandoned, which is a continuation of applicationSer. No. 535,973, filed Sept. 26, 1983, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to novel triazole derivatives which haveantifungal activity and are useful in the treatment of fungal infectionsin animals, including humans, and as agricultural fungicides.

Published United Kingdom Patent Application GB 2,104,065A disclosescompounds of the formula ##STR2## where, inter alia, X is N, n is O, Aris phenyl , R₁, R₂, R₃ are each H, halogen, C₁ -C₃ alkyl or C₁ -C₃alkoxy; R₄ is H, and R is COOR₅, COSR₆, CONR₇ R₈ or CN; and R₇ and R₈are each H, C₁ -C₆ alkyl, C₃ -C₇ cycloalkyl, phenyl or benzyl. Thecompounds are disclosed as useful in combating or preventinginfestations of plants by microorganisms. There is no disclosure ofhuman utility for these compounds.

U.S. Pat. No. 4,394,151 issued July 19, 1983 relates to fungicides andplant growth regulators of the general formula ##STR3## where, interalia, Y is N, R₉ is optionally substituted phenyl, R₁₀ is H or alkyl andR₁₁ is H, alkyl, cycloalkyl, optionally substituted phenyl or optionallysubstituted benzyl or R₉ and R₁₀ taken together form a lactone. Hereagain, no disclosure of human utility is set forth.

European Patent Application No. 69,448 discloses compounds of theformula

    XCH.sub.2 CR.sub.12 R.sub.13 CONR.sub.14 R.sub.15

where, inter alia, X is triazolyl, R₁₂ and R₁₃ are each optionallysubstituted phenyl provided that at least one of R₁₂ and R₁₃ contains atleast one substituent; R₁₄ and R₁₅ are each H, alkyl, cycloalkyl,alkoxyalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, phenyl or benzylor, taken together with the nitrogen atom to which they are attached,they form a pyrrolidinyl, morpholino or a 4-substituted piperazinogroup. They are stated to be useful in treatment of fungal infections inplants, seeds and animals including humans.

European Patent Application No. 54974 discloses imidazole derivatives ofthe formula ##STR4## where Ph is phenyl optionally substituted withhalogen and A is e.g., NR₁₆ R₁₇ where R₁₆ and R₁₇ are each H, alkyl,cycloalkyl, or taken together with the adjacent nitrogen atom they formcertain rings. They are stated to be useful as antifungal agents forhumans.

SUMMARY OF THE INVENTION

invention, there are provided compounds of the formula ##STR5## where

R is phenyl optionally substituted by 1 to 3 substituents eachindependently selected from F, Cl, Br, I, CF₃, C₁ -C₄ alkyl and C₁ -C₄alkoxy, or R is a 5-chloropyrid-2-yl group;

R¹ is --CN, --CSNH₂, or --CONR² R³ where either (a) R² is H or C₁ -C₆alkyl, and R³ is H, C₁ -C₆ alkyl, benzyl, phenethyl, phenyl, --CH₂ CF₃,adamantyl, pyridylmethyl, C₃ -C₇ carbamoylmethyl, (C₂ -C₄alkenyl)methyl, 2-hydroxyethyl, 2-(dimethylamino)ethyl,2-(methylthio)ethyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethylor 2-phenoxyethyl; said benzyl, phenethyl, phenyl and phenoxy groupsbeing optionally ring-substituted by 1 or 2 substituents eachindependently selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, F, Cl, Br, Iand CF₃, (b) R² and R³ taken together with the nitrogen atom to whichthey are attached represent a group of the formula ##STR6## where R⁴ isH, C₁ -C₄ alkyl, C₂ -C₄ alkanoyl or (C₁ -C₄ alkoxy)carbonyl; R⁵ and R⁶are each H or CH₃ ; and their pharmaceutically and agriculturallyacceptable salts, especially their acid addition salts.

The invention also provides a pharmaceutical composition comprising anantifungal amount of a compound of the formula (I) or pharmaceuticallyacceptable acid addition salt thereof, together with a pharmaceuticallyacceptable diluent or carrier.

The invention further provides a compound of the formula (I) orpharmaceutically acceptable acid addition salt thereof, for use intreating fungal infections in animals, including humans.

The invention also includes an agricultural composition suitable for useon a plant or seed comprising an antifungal amount of a compound offormula (I) or agriculturally acceptable acid addition salt thereof,together with an agriculturally acceptable diluent or carrier.

Yet further, the invention provides a method of treating an animal,including a human being, having a fungal infection, which comprisesadministering to the animal an antifungal effective amount of a compoundof the formula (I) or pharmaceutically acceptable acid addition saltthereof.

The invention also includes a method of treating a seed or plant havinga fungal infection, which comprises administering to the plant or seed,or to the locus of said plant, an antifungally effective amount of acompound of the formula (I) or of an agriculturally acceptable acidaddition salt thereof.

When R is said phenyl group it is preferably phenyl substituted by 1 to3 substituents, more preferably 1 or 2 substituents, each independentlyselected from F, Cl, Br, I and CF₃. Particularly preferred values of Rinclude 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl,4-trifluoromethylphenyl, 2-chlorophenyl, 2,4-dichlorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 2-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, 2,4,6-trifluorophenyl and4-bromo-2,5-difluorophenyl.

Even more preferably R is 2,4-dichlorophenyl, 4-chlorophenyl or2,4-difluorophenyl.

R is most preferably 2,4-dichlorophenyl or 2,4-difluorophenyl.

Particularly preferred as R¹ are --CN, --CSNH₂, or CONR² R³ whereineither (a) R² is H, CH₃ or C₂ H₅, and R³ is H, C₁ -C₆ alkyl,p-chlorobenzyl, p-chlorophenethyl, p-methylphenethyl, --CH₂ CF₃,1-adamantyl, 4-pyridylmethyl, cyclopropyl, carbamoylmethyl,--CH₂.CH═CH₂, 2-hydroxyethyl, 2-(dimethylamino)ethyl,2-(methylthio)ethyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,p-chlorophenyl or 2-(p-chlorophenoxy)ethyl; or (b) R² and R³ takentogether with the nitrogen atom to which they are attached represent agroup of the formula: ##STR7##

R¹ is more preferably --CONH₂ or --CONH(C₁ -C₄ alkyl), most preferably--CONH₂, --CONH.CH₃ or --CONH.C₂ H₅.

R⁵ and R⁶ are each preferably H.

In the most preferred individual compounds, R is 2,4-dichlorophenyl or2,4-difluorophenyl; R¹ is --CONH₂, --CONHCH₃ or --CONHC₂ H₅ ; and R⁵ andR⁶ are H.

In one aspect of the invention, there are provided compounds of theformula: ##STR8## where

R is phenyl optionally substituted by 1 to 3 substituents eachindependently selected from F, Cl, Br, I, CF₃, C₁ -C₄ alkyl and C₁ -C₄alkoxy, or R is a 5-chloro-pyrid-2-yl group; and

R¹ is --CN or --CONR² R³ where R² is H, or C₁ -C₆ alkyl, and R³ is H, C₁-C₆ alkyl, benzyl, --CH₂ CF₃ or adamantyl, said benzyl group beingoptionally substituted on its phenyl ring portion by 1 or 2 substituentseach independently selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, F, Cl, Br,I and CF₃, or R² and R³ taken together with the nitrogen atom to whichthey are attached represent a group of the formula ##STR9## where R⁴ isH, C₁ -C₄ alkyl, C₂ -C₄ alkanoyl or (C₁ -C₄ alkoxy)carbonyl; and theirpharmaceutically acceptable salts.

In another aspect of the invention, there are provided compounds of theformula: ##STR10## where R is phenyl optionally substituted by 1 to 3substituents each independently selected from F, Cl, Br, I, CF₃, C₁ -C₄alkyl and C₁ -C₄ alkoxy, or R is a 5-chloropyrid-2-yl group; R¹ is --CNor --CONR² R³ where R² is H, or C₁ -C₆ alkyl , and R³ is H, C₁ -C₆alkyl, benzyl, --CH₂ CF₃ or adamantyl, said benzyl group beingoptionally substituted on its phenyl ring portion by 1 or 2 substituentseach independently selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, F, Cl, Br,I and CF₃, or R² and R³ taken together with the nitrogen atom to whichthey are attached represent a group of the formula ##STR11## where R⁴ isH, C₁ -C₄ alkyl, C₂ -C₄ alkanoyl or (C₁ -C₄ alkoxy)carbonyl; and R⁵ is Hor CH₃ ; and their pharmaceutically acceptable salts.

Where the compounds of formula (I) contain at least one chiral center,the invention includes both the resolved and unresolved forms.

The invention also includes the novel intermediates of the formula:##STR12## where R, R⁵ and R⁶ are as previously defined for formula (I).

Other useful intermediates have the formula: ##STR13## where R, R⁵ andR⁶ are as defined for formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula (I) are prepared, for example, as illustratedbelow.

(1) Compounds in which R¹ is --CN and R⁵ and R⁶ are H are prepared bythe following general method: ##STR14##

The preferred source of cyanide ions are the alkali metal cyanides,particularly sodium and potassium cyanide. In a typical procedure, thecompound (II) and sodium or potassium cyanide are heated together in asuitable organic solvent, e.g. dimethylformamide, at up to 100° C.,preferably 65°-70° C., for up to 6 hours. It is preferred to add thecyanide dropwise to the solution of the oxirane over about a half-hour.After cooling the reaction mixture and pouring it into water, thedesired product is isolated and purified by conventional techniques.

The starting materials of the formula (II) are in many cases knowncompounds (see e.g., European Patent Application Publication No. 44605)or can be prepared by routine methods as will be known to those skilledin the art, for example, ##STR15##

(2) Compounds in which R¹ is --CN and R⁵ and R⁶ are each H or CH₃ areprepared, for example, by the following general route ##STR16##

The preferred strong base in n-butyllithium. In a typical procedure, thenitrile is dissolved in a suitable solvent, e.g., dry tetrahydrofuran(THF), and the resulting solution is then cooled to about -70° C. Asolution of n-butyllithium in hexane is then slowly added dropwise.After stirring for about an hour at -70° C., the ketone (III) in asuitable solvent, e.g., dry THF, is slowly added dropwise. Afterstirring for about an hour at -70° C. glacial acetic acid in a littleTHF is added and the reaction mixture is allowed to warm to 0° C. Theproduct is then isolated and purified conventionally. When one of R⁵ andR⁶ is H and the other is CH₃, the product will exist in twodiastereoisomeric forms and these are often separated by chromatography.

The starting materials of the formula (III) are either known compoundsor can be prepared by conventional methods.

(3) Compounds in which R¹ is --CONH₂ and R⁵ and R⁶ are H are prepared,for example, as follows: ##STR17##

Preferable compound (IV) is used in its ethyl ester form. The acid ispreferably supplied by using compound (IV) in an acid addition saltform, e.g. as the dihydrochloride. Alternatively, the free base is usedand hydrogen chloride gas bubbled into the solution to form the salt.Typically the reactants are heated together for a short period,preferably under reflux, in a suitable high-boiling organic solvent suchas 1,2-dichlorobenzene (b.p. 178° C.), the reaction is usually completein about 15 minutes.

The starting materials of the formula (IV) are obtainableconventionally, e.g. as follows: ##STR18##

(4) Compounds in which R¹ is --CONH(C₁ -C₄ alkyl) or --CON(C₁ -C₄alkyl)₂ are prepared by the alkylation of the corresponding startingmaterials in which R¹ is --CONH₂. The alkylation is typically carriedout by dissolving the starting material in a suitable organic solvent,e.g. dry THF, followed by cooling to 0°-5° C. A strong base such assodium hydride is then added. After stirring for a few minutes, anappropriate quantity of alkylating agent is added. The preferredalkylating agents are the alkali metal iodides and bromides. Formono-alkylation, only one equivalent of alkylating agent should be used,and, for dialkylation, at least 2 equivalents. The alkylated product isisolated from the reaction mixture by conventional techniques.

(5) Compounds in which R¹ is --CONR² R³ where R² R³ are as defined in(a) or (b) in formula (I) can also be prepared as follows: ##STR19##

Compound (V) is preferably used in the form of its functional equivalentas an acylating agent, e.g. as an acid chloride or bromide, a mixedanhydride of the formula ##STR20## or as a C₁ -C₄ alkyl, succinimido,phthalimido or benzotriazol-1-yl ester.

All these functional equivalents are prepared conventionally from theacid (V). The acid chlorides and bromides are, for example, prepared byreaction of the acid of formula (V) with thionyl chloride or bromide,the mixed anhydrides by reaction with a C₂ -C₅ alkanoyl chloride, the C₁-C₄ alkyl esters by simple esterification, and the succinimido,phthalimido and benzotriazol-1-yl esters by reaction withN-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxybenzotriazole inthe presence of a dehydrating agent such as dicyclohexylcarbodiimide.

In fact, it is preferred to use the compounds (V) in the form of theirsuccinimido esters of the formula: ##STR21## Thus in a typicalprocedure, dicyclohexylcarbodiimide dissolved in e.g. dry dioxan isadded to a solution of the acid (V) and N-hydroxysuccinimide in e.g. drydioxan. After stirring for a few hours at room temperature andfiltering, the reaction is generally completed by stirring the solutionof the compound (VII) with the amine R² R³ NH at room temperature for afew hours in e.g. dry dioxan, after which the product is isolated andpurified by conventional means.

If compound (V) is reacted in its free acid form, the reaction shouldgenerally be carried out in the presence of a dehydrating agent such asdicyclohexylcarbodiimide.

The C₁ -C₄ alkyl esters can also be prepared as follows: ##STR22##

Generally some of the product (VIII) cyclises in situ under the reactionconditions to give the intermediate lactone (A). Mixtures of the ester(VIII) and lactone (A) are separated e.g. by column chromatography.

The benzotriazol-1-yl esters have the formula: ##STR23##

These are prepared as discussed above.

Thus in a typical procedure, dicyclohexylcarbodiimide,1-hydroxybenzotriazole and the acid (V) are stirred together at roomtemperature for a short period in e.g. dry dioxan. The reaction isgenerally completed by stirring the resulting imtermediate (IX) with theamine R² R³ NH at room temperature until the reaction is complete, afterwhich the product is isolated and purified by conventional means.

(6) Compounds of the formula (I) in which R¹ is --CONH₂ are prepared bythe controlled hydrolysis of the corresponding compounds in which R¹ is--CN. Typically this hydrolysis is carried out by heating the startingnitrile at about 70°-100° C., preferably 90°-95° C., with aqueoussulphuric acid, preferably 80%, by weight, until the formation of theamide is complete as monitored by thin-layer chromatography.

Further hydrolysis to convert --CONH₂ to --COOH, if desired, is carriedout under similar conditions. The compounds in which R¹ is --COOH areuseful intermediates (see route (5) above, for example).

(7) The amides of the formula (I) in which R¹ is --CONR² R³ where R² andR³ are as defined in (a) or (b) for formula (I) are also prepared fromthe intermediates of the formula (A) as follows: ##STR24## where R, R²,R³, R⁵ and R⁶ are as defined for formula (I).

The reaction is carried out by stirring the reactants together in asuitable solvent, e.g. ethanol, at room temperature until the reactionis complete. If necessary, the mixture is heated to accelerate thereaction. The product is then isolated and purified conventionally.

(8) Compounds in which R³ is 2-(methylsulphinyl)ethyl and2-(methylsulphonyl)ethyl are prepared e.g. by the oxidation of thecorresponding 2-(methylthio)ethyl compounds using the appropriatequantity of oxidizing agent, e.g. m-chloroperbenzoic acid, inconventional manner.

(9) Compounds in which R¹ is --CSNH₂ are prepared e.g. as outlinedbelow: ##STR25##

The reaction is typically carried out by heating the reactants at up toabout 100° C. in the presence of water. The product is then isolated byconventional methods.

(10) Compounds in which R¹ is --CONH₂ and R⁵ and R⁶ are H are alsoprepared as shown below: ##STR26##

The reaction is typically carried out by stirringbis(trimethylsilyl)acetamide at -70° C. in dry tetrahydrofuran (THF)while n-butyllithium is slowly added dropwise. The resulting solution isstirred at about -70° C. for a short period, then the ketone (III) ine.g. dry THF is slowly added, and the resulting mixture stirred at about-70° C. for a few hours. The reaction mixture is then allowed to warm toroom temperature and aqueous acid is added. The product is then isolatedand purified conventionally.

(11) Amides of formula (I) in which R² and R³ together with the nitrogenatom to which they are attached represent aziridinyl are prepared e.g.as follows: ##STR27##

The reaction is generally carried out at room temperature in thepresence of an organic solvent, e.g. dry tetrahydrofuran.

(12) The lactone intermediates of the formula (A) are prepared bycyclization, preferably using an ester according to the followingscheme: ##STR28## where Q═C₁ -C₂ alkyl, phthalimido, succinimido or1-benzotriazolyl.

These esters are prepared as previously described. The cyclization iscarried out e.g. in the presence of a suitable base by stirring at roomtemperature. Preferred bases are tertiary amine bases, e.g.triethylamine, and alkali metal hydrides, e.g. sodium hydride.

The compounds of the invention contain a chiral center or centers andthe invention includes both the resolved and unresolved forms.

Pharmaceutically acceptable acid addition salts of the compounds of theformula (I) are those formed from strong acids which form non-toxic acidaddition salts, such as hydrchloric, hydrobromic, sulfuric, oxalic andmethanesulfonic acids.

The salts are obtained by conventional procedures, e.g., by mixingsolutions containing equimolar amounts of the free base and desiredacid, and the required salt is collected by filtration, if insoluble, orby evaporation of the solvent.

Also included are the alkali metal salts, preparable conventionally.

The compounds of the formula (I) and their pharmaceutically acceptablesalts are antifungal agents, useful in combating fungal infections inanimals, including humans For example, they are useful in treatingtopical fungal infections in man caused by, among other organisms,species of Candida, Trichophyton, Microsporum or Epidermophyton, or inmucosal infections caused by Candida albicans (e.g., thrush and vaginalcandidiasis). They are also useful in the treatment of systemic fungalinfections caused by, for example, Candida albicans, Cryptococcusneoformans, Aspergillus fumigatus, Coccidioides, Paracoccidioides,Histoplasma or Blastomyces.

The in vitro evaluation of the antifungal activity of the compounds iscarried out, e.g., by determining the minimum inhibitory concentration(m.i.c.), which is the concentration of the test compound in a suitablemedium at which growth of the particular microorganism fails to occur.In practice, a series of agar plates, each having the test compoundincorporated at a particular concentration is inoculated with a standardculture of, for example, Candida albicans and each plate is thenincubated for 48 hours at 37° C. The plates are then examined for thepresence or absence of growth of the fungus and the appropriate m.i.c.value is noted. Other microorganisms used in such tests include, e.g.,Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton spp;Microsporum spp; Epidermophyton floccosum, Coccidioides immitis andTorulopsis glabrata.

The in vivo evaluation of the compounds is carried out, e.g., at aseries of dose levels by intraperitoneal or intravenous injection or byoral administration to mice which are inoculated with a strain ofCandida albicans. Activity is based on the survival of a treated groupof mice after the death of an untreated group of mice following 48 hoursobservation. The dose level at which the compound provides 50%protection (PD₅₀) against the lethal effect of the infection is noted.

The in vivo oral PD₅₀ values for selected compounds of the invention,obtained with mice inoculated with a lethal dose of Candida albicans bythe method described above, are summarized in the table below. Values inparenthesis were obtained in separate determinations

    ______________________________________                                         ##STR29##                     (I)                                            where R = 2,4-Cl.sub.2 C.sub.6 H.sub.3, R.sup.5 = R.sup.6                     ______________________________________                                        = H:                                                                                              Example  Oral PD.sub.50                                   R.sup.1             No.      (mg/kg)                                          ______________________________________                                        CN                  1, 2     1.3 (1.3)                                        CONH.sub.2          4, 44, 45                                                                              0.2 (0.2) (0.2)                                  CONHCH.sub.3        5, 7, 43B                                                                              0.2 (˜0.4) (0.2)                            ##STR30##          6        ˜20                                        CONHCH(CH.sub.3).sub.2                                                                            8        0.1                                              CON(CH.sub.3).sub.2 9        0.4                                               ##STR31##          10       0.1                                               ##STR32##          11       ˜30                                         ##STR33##          12       3.1                                               ##STR34##          13       ˜40                                        CON(C.sub.2 H.sub.5).sub.2                                                                        14       0.4                                              CONHC.sub.2 H.sub.5 15       0.2                                              CONH(1-admantyl)    16       ˜20                                        CONHCH.sub.2 -4-pyridyl                                                                           17       1.5                                              CONHCH.sub.2 CF.sub.3                                                                             18       0.4                                              CONH(CH.sub.2).sub.5 CH.sub.3                                                                     19       2.2                                              CONH-cyclopropyl    20       0.1                                              CONHCH.sub.2 CH.sub.2 -4-ClC.sub.6 H.sub.4                                                        21       0.6                                              CONH(CH.sub.2).sub.2 CH.sub.3                                                                     22       0.2                                              CONHCH.sub.2 CHCH.sub.2                                                                           24       0.4                                              CONHCH.sub.2 C(CH.sub.3).sub.3                                                                    25       3.5                                              CONHCH.sub.2 CH.sub.2 OH                                                                          26       2.2                                              CONH(CH.sub.2).sub.2 -4-CH.sub.3 C.sub.6 H.sub.4                                                  27       4.2                                              CONH(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                            28       4.2                                               ##STR35##          29       4.2                                              CONHCH.sub.2 CH.sub.2 SCH.sub.3                                                                   30       0.1                                               ##STR36##          31       3.1                                              CON(CH.sub.3)CH(CH.sub.3).sub.2                                                                   32       0.2                                              CONHCH.sub.2 CH.sub.2 S(O)CH.sub.3                                                                47       0.2                                              CONHCH.sub.2 CH.sub.2 S(O.sub.2)CH.sub.3                                                          48       0.1                                               ##STR37##          49       4.2                                              CSNH.sub.2          50       0.5                                              ______________________________________                                                                       Example                                                                              Oral PD.sub.50                          R.sup.1 R          R.sup.5                                                                              R.sup.6                                                                            No.    (mg/kg)                                 ______________________________________                                        CONHCH.sub.3                                                                          2,4-F.sub.2 C.sub.6 H.sub.3                                                              H      H    33     0.3                                     CN      2,4-Cl.sub.2 C.sub.6 H.sub.3                                                             H      CH.sub.3                                                                           34     0.1                                     CN      4-ClC.sub.6 H.sub.4                                                                      H      CH.sub.3                                                                           35     2.0                                     CONH.sub.2                                                                            2,4-Cl.sub.2 C.sub.6 H.sub.3                                                             H      CH.sub.3                                                                           37     0.4                                     CONH.sub.2                                                                            2,4-F.sub.2 C.sub.6 H.sub.3                                                              H      CH.sub.3                                                                           38     0.4                                     CONH.sub.2                                                                            4-ClC.sub.6 H.sub.4                                                                      H      CH.sub.3                                                                           39     0.5                                     CONHCH.sub.3                                                                          2,4-Cl.sub.2 C.sub.6 H.sub.3                                                             H      CH.sub.3                                                                           40     0.2                                     CONH.sub.2                                                                            2,4-Cl.sub.2 C.sub.6 H.sub.3                                                             CH.sub.3                                                                             CH.sub.3                                                                             41D  3.1                                     CONHCH.sub.3                                                                          2,4-Cl.sub.2 C.sub.6 H.sub.3                                                             CH.sub.3                                                                             CH.sub.3                                                                           42     0.6                                     ______________________________________                                    

For human use, the antifungal compounds of the formula (I) can beadministered alone, but will generally be administered in admixture witha pharmaceutical carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice. For example, theycan be administered orally in the form of tablets containing suchexcipients as starch or lactose, or in capsules or ovules either aloneor in admixture with excipients, or in the form of elixirs orsuspensions containing flavoring or coloring agents. They can beinjected parenterally, for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other substances,for example, enough salts or glucose to make the solution isotonic withblood.

For oral or parenteral administration to human patients, the dailydosage level of the antifungal compounds of the formula (I) will be from0.1 to 5 mg/kg (in divided doses) when administered by either the oralor parenteral route. Thus tablets or capsules of the compounds willcontain from 5 mg. to 0.5 g of active compound for administration singlyor two or more at a time as appropriate. The physician in any event willdetermine the actual dosage which will be most suitable for anindividual patient and it will vary with the age, weight and response ofthe particular patient. The above dosages are exemplary of the averagecase; there can, of course, be individual instances where higher orlower dosage ranges are merited, and such are within the scope of thisinvention.

Alternatively, the antifungal compounds of formula (I) are administeredin the form of a suppository or pessary, or they are applied topicallyin the form of a lotion, solution, cream, ointment or dusting powder.For example, they are incorporated into a cream consisting of an aqueousemulsion of polyethylene glycols or liquid paraffin; or incorporated, ata concentration between 1 and 10%, into an ointment consisting of awhite wax or white soft paraffin base together with such stabilizers andpreservatives as may be required.

The compounds of the formula (I) and their salts also have activityagainst a variety of plant pathogenic fungi, including for examplevarious rust, mildews and molds, and the compounds are thus useful fortreating plants and seeds to eradicate or prevent such diseases.

The in vitro evaluation of the activity of the compounds against plantfungi is determined, e.g., by measuring their minimum inhibitoryconcentrations in the same way as previously described except that theplates are incubated at 30° C. for 48 hours or longer before beingexamined for the presence or absence of growth.

Microorganisms used in such tests include Cochliobolus carbonum,Pyricularia oryzae, Glomerella cingulata, Penicillium digitatum,Botrytis cinerea and Rhizoctonia solani.

For agricultural and horticultural purposes the compounds and theiragriculturally acceptable salts are preferably used in the form of acomposition formulated as appropriate to the particular use and purposedesired. Thus the compounds are applied in the form of dusting powders,or granules, seed dressings, aqueous solutions, dispersions oremulsions, dips, sprays, aerosols or smokes. Compositions are alsoapplied in the form of dispersible powders, granules or grains, orconcentrates for dilution prior to use. Such compositions may containsuch conventional carriers, diluents or adjuvants as are known andacceptable in agriculture and horticulture and they are manufactured inaccordance with conventional procedures. The compositions may alsoincorporate other active ingredients, for example, compounds havingherbicidal or insecticidal activity or a further fungicide. Thecompounds and compositions can be applied in a number of ways, forexample, they are applied directly to the plant foilage, stems,branches, seeds or roots or to the soil or other growing medium, andthey can be used not only to eradicate disease, but alsoprophylactically to protect the plants or seeds from attack.

The following Examples illustrate the invention. All temperatures are in° C. Mixtures of solvents employed for chromatography are by volume.

EXAMPLE 11-Cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol##STR38##

To 2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (6.7 g)in dimethylformamide (198 ml) at 60° C. was added dropwise over 25minutes a solution of sodium cyanide (2.84 g) in water (49 ml). Heatingat 60° C. was continued for five hours. The reaction mixture was thencooled, poured into water (900 ml), and extracted with ethyl acetate(3×150 ml). The combined organic extracts were washed with saturatedaqueous brine, dried (Na₂ SO₄ ) and evaporated to dryness to give a paleyellow solid (6.1 g) which was triturated with ethyl ether. The residualsolid was recrystallized from ethyl ether/methanol to give the titlecompound, 4.13 g (56%), m.p. 217°-219° C.

Analysis %:

Found: C, 48.3; H, 3.4; N, 18.4.

Calculated for C₁₂ H₁₀ Cl₂ N.sub. O: C, 48.5; H, 3.4; N, 18.8.

EXAMPLE 21-Cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol##STR39##

Acetonitrile (2.25 g, 0.055 mole) was dissolved in dry tetrahydrofuran(100 ml) and the resulting solution was cooled to -70° C. under nitrogenin an acetone/dry ice bath. A solution of n-butyllithium in hexane (39ml, 1.55 molar, 0.060 mole) was added dropwise over five minutes. Afterstirring for about 45 minutes at -70° C.,2',4'-dichloro-2-(1H-1,2,4-triazol-1-yl)acetophenone (12.8 g) in drytetrahydrofuran (100 ml) was added dropwise over a 15 minute period.Stirring was continued at -70° C. for about one hour and then glacialacetic acid (20 ml) in tetrahydrofuran (20 ml) was added dropwise. Thecooling bath was then removed. The reaction mixture was allowed to warmto 0° C., quenched in water (400 ml), and solid sodium carbonate wasadded to raise the pH to 8.0. After extraction with ethyl acetate (3×75ml), the combined organic extracts were washed with saturated brine(3×50 ml), dried (Na₂ SO₄) and evaporated to a pale yellow solid. Thissolid was washed well with ethyl ether to give the title compound (6.61g, 44.5%), identical to the product of Example 1 as confirmed by n.m.r.and i.r. spectroscopy.

EXAMPLE 3

1-Cyano-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol wasprepared similarly to the previous Example using2',4'-difluoro-2-(1H-1,2,4-triazol-1-yl)acetophenone as the startingketone. It had an m.p. of 154°-155° C.

Analysis %:

Found C, 54.0; H, 3.8; N, 21.5.

Calculated for C₁₂ H₁₀ F₂ N₄ O: C, 54.6; H, 3.8; N, 21.2.

EXAMPLE 41-Carbamoyl-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol##STR40##

3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrimidicacid, ethyl ester dihydrochloride (3.42 g) was suspended in1,2-dichlorobenzene (35 ml) and the mixture was heated to the refluxtemperature of the solvent [178° C.). After refluxing for five minutes,a solution was obtained. Refluxing was then continued for an additional10 minutes. The reaction mixture was cooled, evaporated, and theresulting gum was triturated with hexane and heated with acetone. Oncooling a cream-colored granular solid was formed which was filtered toyield the title compound as a solvate (1.26 g). On standing overnight ina refrigerator some further solvated product precipitated (0.62 g).After drying at 80° C. for 6 hours to remove the solvent the pure(unsolvated) title compound was obtained, yield 1.5 g, m.p. 144°-145° C.

Analysis % (after said drying):

Found: C, 45.5; H, 3.8; N, 17.5.

Calculated for C₁₂ H₁₂ Cl₂ N₄ O₂ : C, 45.7; H, 3.8; N, 17.8.

EXAMPLE 52-(2,4-Dichlorophenyl)-1-(N-methylcarbamoyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol##STR41##

1-Carbamoyl-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol(1.0 g) was dissolved in dry tetrahydrofuran (20 ml) and the reactionmixture was cooled to 0°-5° C. Sodium hydride (0.15 g, as a 50%dispersion in oil) was then added, the mixture stirred for 10 minutesand methyl iodide (0.45 g) added. Further quantities of methyl iodide(90 mg) and sodium hydride (375 mg, as a 50% dispersion in oil) wereadded. After stirring for a few minutes, yet further quantities ofmethyl iodide (90 mg) and sodium hydride (375 mg, as a 50% dispersion inoil) were added. The mixture was then quenched in water and extractedwith ethyl acetate (3×50 ml). The combined organic extracts were dried(MgSO₄) and evaporated to give the crude product as a gum. A solution ofthis gum in methylene chloride (20 ml) was chromatographed on a silicagel column (10 g), eluting with methylene chloride (100 ml), then withmethylene chloride containing 2% isopropanol and 0.2% NH₄ OH (300 ml),and finally with methylene chloride containing 5% isopropanol and 0.5%NH₄ OH (500 ml). Appropriate fractions were collected to yield the titlecompound, which was recrystallized from cyclohexane (yield 41 mg, m.p.151°-154° C.).

Analysis %:

Found: C, 47.3; H, 4.35; N, 17.2.

Calculated for C₁₃ H₁₄ Cl₂ N₄ O₂ : C, 47.4; H, 4.3; N, 17.0.

EXAMPLE 62-(2,4-Dichlorophenyl)-1-(morpholinocarbonyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-olmonohydrate A.1-Carboxy-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1yl)propan-2-ol

1-Cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol (4g, 13.9 mmole) was dissolved in 40% aqueous sulfuric acid (100 ml) andheated in an oil bath at 100°-110° C. for 18 hours. The solution wasthen cooled, diluted with water (200 ml), and rendered alkaline by theslow addition of solid sodium bicarbonate. The mixture was thenextracted several times with ethyl acetate (3×100 ml) and the aqueousphase was rendered acidic (pH 3) by the addition of diluteorthophosphoric acid. The aqueous phase was then extracted with ethylether (3×150 ml), the combined ether extracts were washed once withwater, and then dried over magnesium sulfate. Evaporation of the ethergave the title compound as a pale yellow solid, 2.7 g, (62%), m.p.158°-159° C.

Analysis %:

Found: C, 46.35; H, 3.5; N, 13.6.

Required for C₁₂ H₁₁ Cl₂ N₃ O₃ : C, 45.6; H, 3.5; N, 13.3.

N,N'-Dicyclohexylcarbodiimide ("DCCD") (110 mg, 0.5 mmole) dissolved indry dioxan (5 ml) was added to a solution of1-carboxy-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol(150 mg, 0.5 mmole) and N-hydroxysuccinimide ("NHS") (60 mg, 0.5 mmole)in dry dioxan (10 ml), and the mixture was stirred at room temperaturefor 2 hours. The precipitate was filtered off, washed with dry dioxan(10 ml) and the combined filtrate and washings were then added to asolution of morpholine (300 mg, 3.4 mmole) in dry dioxan (2 ml). Theresultant solution was left at room temperature for 18 hours, dilutedwith ethyl acetate (100 ml), washed three times with saturated brinesolution and dried over magnesium sulfate. Evaporation of the filtrategave an oil (300 mg) which was then chromatographed on "Kieselgel 60H"(Merck, Trade Mark) silica (10 g), eluting with methylene chloridecontaining 2% isopropyl alcohol and 0.2% aqueous ammonium hydroxide (Sp.gr. 0.880). The title compound was obtained after evaporation ofappropriate fractions as a colorless solid, 110 mg (57%), m.p. 92°-93°C.

Analysis %:

Found: C, 47.8; H, 4.7; N, 13.9.

Required for C₁₆ H₁₈ N₄ Cl₂ O₃.H₂ O: 47.8; H, 5.0; N, 13.9.

EXAMPLES 7-32

The following compounds were prepared similarly to the previous Example,starting from the same acid, DCDD/NHS and the appropriate amine:

    __________________________________________________________________________     ##STR42##                                                                                                  Analysis %                                      Example                       Theoretical in brackets                         No.  R.sup.1            m.p. (°C.)                                                                   C   H   N                                       __________________________________________________________________________    7    CONHCH.sub.3       151-3°                                                                       (Identical to the                                                             product of Example 5)                           8    CONHCH(CH.sub.3).sub.2                                                                           105-107°                                                                     50.7                                                                              5.2 15.3                                                                  (50.6                                                                             5.1 15.7)                                   9    CON(CH.sub.3).sub.2                                                                              125-126.5°                                                                   48.95                                                                             4.65                                                                              16.3                                                                  (49.1                                                                             4.7 16.4)                                   10                                                                                  ##STR43##         glass,  64-65°                                                               52.15 (52.05                                                                      3.95 3.9                                                                          12.5 12.8)                                                            (As trihydrate)                                 11                                                                                  ##STR44##         glass,  63-5°                                                                45.3 (45.1                                                                        4.4 5.6                                                                           14.4 14.6)                                                            (As hemihydrate)                                12                                                                                  ##STR45##         glass,  58-60°                                                               49.2 (49.1                                                                        5.1 5.2                                                                           15.0 15.1)                              13                                                                                  ##STR46##         glass,  40-41°                                                               52.4 (52.2                                                                        5.05 4.9                                                                          15.0 15.2)                              14   CON(C.sub.2 H.sub.5).sub.2                                                                       glass,                                                                              51.9                                                                              5.5 15.0                                                             60-62°                                                                      (51.8                                                                             5.4 15.1)                                   15   CONHC.sub.2 H.sub.5                                                                              129-130°                                                                     49.0                                                                              4.8 15.8                                                                  (49.0                                                                             4.7 16.3)                                   16   CONH(1-adamantyl)   91-92°                                                                      58.7                                                                              6.1 12.0                                                                  (58.8                                                                             5.8 12.5)                                                                 (As hemihydrate)                                17                                                                                  ##STR47##         glass,  48-50°                                                               52.3 (52.1                                                                        4.2 4.3                                                                           16.5 16.8)                              18   CONHCH.sub.2 CF.sub.3                                                                            glass,                                                                              42.6                                                                              3.5 13.6                                                             60-62°                                                                      (42.3                                                                             3.3 14.1)                                   19   CONH(CH.sub.2).sub.5 CH.sub.3                                                                    114-116°                                                                     54.2                                                                              6.1 14.1                                                                  (54.1                                                                             6.1 14.0)                                   20                                                                                  ##STR48##         122-123°                                                                     50.6 (50.7                                                                        4.6 4.5                                                                           15.6 15.8)                              21                                                                                  ##STR49##         142-143°                                                                     52.9 (52.9                                                                        4.2 4.2                                                                           12.2 12.3)                                                            (As hydrochloride)                              22   CONH(CH.sub.2).sub.2 CH.sub.3                                                                    169-170°                                                                     45.7                                                                              4.8 14.0                                                                  (45.8                                                                             4.9 14.2)                                                                 (As hydrochloride                                                             hemihydrate)                                    23   CONHCH.sub.2 CONH.sub.2                                                                          188-191°                                                                     40.6                                                                              4.05                                                                              16.9                                                                  (40.2                                                                             4.1 16.8)                                                                 (As oxalate 1/2 hydrate)                        24   CONHCH.sub.2CHCH.sub.2                                                                           glass  45.4                                                                             4.3 12.0                                                                  (45.4                                                                             4.1 12.4)                                   25   CONHCH.sub.2 C(CH.sub.3).sub.3                                                                   135-137°                                                                     53.2                                                                              5.9 14.7                                                                  (53.0                                                                             5.8 14.5)                                                                 (As 1/4 hydrate)                                26   CONHCH.sub.2 CH.sub.2 OH                                                                         143-145°                                                                     46.1                                                                              4.4 15.3                                                                  (46.2                                                                             4.6 15.4)                                   27                                                                                  ##STR50##         144-145°                                                                     58.2 (58.2                                                                        5.1 5.1                                                                           12.8 12.9)                                                            (As dihydrochloride                                                           dihydrate)                                      28   CONH(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                           107-110°                                                                     38.8                                                                              5.2 13.6                                                                  (38.8                                                                             5.1 14.2)                                                                 (Contains 1 mole of                                                           cyclohexane)                                    29                                                                                  ##STR51##         102-105°                                                                     56.6 (56.6                                                                        5.4 5.3                                                                           10.9 11.0)                              30   CONHCH.sub.2 CH.sub.2 SCH.sub.3                                                                  154-156°                                                                     42.6                                                                              4.5 13.3                                                                  (42.3                                                                             4.5 13.2)                                   31                                                                                  ##STR52##         137-9°                                                                       51.0 (51.1                                                                        4.0 4.1                                                                           11.9 11.9)                              32   CON(CH.sub.3)(CH[CH.sub.3 ].sub.2)                                                               131-2°                                                                       51.7                                                                              5.3 15.2                                                                  (51.8                                                                             5.4 15.1)                                   __________________________________________________________________________

EXAMPLE 33

The following compound was prepared by the procedure of Example 6,starting from1-carboxy-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-propan-2-ol,"DCCD", "NHS" and methylamine: ##STR53##

It melted at 129°-131° C.

Analysis %:

Found: C, 52.8; H, 4.9; N, 19.3.

Calculated for C₁₃ H₁₄ F₂ N₄ O₂ : C, 52.7; H, 4.8; N, 18.9.

EXAMPLE 343-Cyano-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (2diastereoisomeric forms) ##STR54##

Propionitrile (1.21 g) in dry tetrahydrofuran (50 ml) was cooled to -72°C. A solution of n-butyllithium in n-hexane (14.2 ml, 1.55 molar) wasthen slowly added while maintaining the temperature of the reactionmixture at -45° C. or below. After stirring for about 30 minutes,2-(1H-1,2,4-triazol-1-yl)-2',4'-dichloroacetophenone (2.56 g) in drytetrahydrofuran (THF) (50 ml) was added slowly with stirring over a 20minute period, the temperature of the mixture being maintained at -70°C. Stirring was continued at this temperature for one hour and then at-10° for a half hour, then glacial acetic acid (10 ml) in dry THF (15ml) was added. The reaction mixture was allowed to warm to roomtemperature (20° C.), adjusted to pH 8 with solid sodium bicarbonate,and extracted with ethyl acetate (3×75 ml). The combined organicextracts were washed three times with water, dried (MgSO₄), evaporatedand ethyl ether (30 ml) was added to the residue, yielding a whitecrystalline solid and a yellow solution. The solid was filtered off,dissolved in a small volume of methylene chloride, and loaded onto an 18g flash chromatography column of Merck's "Kieselgel 60" (Trade Mark)230-400 mesh silica in ether (11×2 cm. diameter). Elution was carriedout using 5% (by volume) acetone in ether at one p.s.i. (0.07 kg/m²)"Diastereoisomer 1" of the title compound was eluted first, 0.79 g, m.p.178°-180° C.

Analysis %:

Found: C, 50.0; H, 3.8; N, 17.9.

Calculated for C₁₃ H₁₂ Cl₂ N₄ O: C, 50.2; H, 3.9; N, 18.0.

"Diastereoisomer 2" of the title compound was eluted next, 0.244 g, m.p.202°-205° C.

Analysis %:

Found: C, 50.4; H, 3.9; N, 17.6.

Calculated for C₁₃ H₁₂ Cl₂ N₄ O: C, 50.2; H, 3.9; N; 18.0.

EXAMPLES 35 and 36

The following compounds were prepared similarly to the previous Example,starting from the appropriate acetophenone, n-BuLi/C₂ H₅ CN and glacialacetic acid.

    ______________________________________                                         ##STR55##                                                                                                Analysis %                                        Example            m.p.     Theoretical in Brackets                           No.    R           (°C.)                                                                           C      H     N                                    ______________________________________                                        35                                                                                    ##STR56##  159-162°                                                                        56.4 (56.4                                                                           4.8 4.7                                                                             20.0 20.2)                           36                                                                                    ##STR57##  185-187°                                                                        56.2 (56.1                                                                           4.3 4.3                                                                             20.0 20.1)                           ______________________________________                                    

EXAMPLE 373-Carbamoyl-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olhemihydrate and3-carboxy-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

3-Cyano-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-yl)butan-2-ol (700mg, diastereoisomer 1 from the previous Example) was heated for 51/2hours at 90°-95° C. in 40% (by volume) aqueous sulfuric acid. Thesolution was then stirred at room temperature (20° C.) for 19 hours,after which time saturated aqueous sodium bicarbonate solution was addedto raise the pH to 8.0. The solution was then extracted with ethylacetate (3×50 ml). The combined organic extracts were washed with water,dried (MgSO₄) and evaporated to yield the 3-carbamoyl title compound,105 mg, m.p. 215°-217° C. after trituration with ethyl ether.

Analysis %: (3-carbamoyl compound)

Found: C, 46.8; H, 4.5; N, 15.5.

Calculated for C₁₃ H₁₄ Cl₂ N₄ O₂.1/4H₂ O:

C, 46.2; H, 4.5; N, 15.6.

The aqueous phases resulting from the ethyl acetate extractions werecombined, acidified to pH 2.0 with dilute hydrochloric acid, andextracted with ethyl acetate (3×50 ml). The combined organic extractswere washed with water, dried (MgSO₄) and evaporated to yield the titleacid. After trituration with ethyl ether, the pure acid, 485 mg, m.p.236°-238° C., was obtained.

Analysis %:

Found: C, 47.0; H, 3.9; N, 12.4.

Calculated for C₁₃ H₁₃ Cl₂ N₃ O₃ : C, 47.3; H, 4.0; N, 12.7.

EXAMPLE 38

3-Carbamoyl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol1/4 hydrate, m.p. 170°-172° C., was prepared similarly to the previousExample by the hydrolysis of the corresponding nitrile prepared inExample 36 but using 80% (w/w) aqueous sulfuric acid.

Analysis %:

Found: C, 52.0; H, 4.8; N, 18.5.

Calculated for C₁₃ H₁₄ F₂ N₄ O₂.1/4H₂ O:

C, 51.9; H, 4.8; N, 18.6.

EXAMPLE 392-(4-Chlorophenyl)-3-carbamoyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

The mixture of diastereomeric nitriles from Example 35 (3.9 g) washeated in sulfuric acid (80% by weight, 100 ml) for four hours at 60° C.The reaction mixture was then cooled, diluted with water (200 ml), andcalcium carbonate (50 g) was added in small portions with externalcooling (ice bath). The mixture was then filtered, and the materialwhich had been filtered off was washed well with water (200 ml) andmethanol (200 ml). The washings were added to the filtrate, evaporatedto dryness, and the residue extracted with ethyl acetate (3×100 ml). Theextracts were combined, dried (MgSO₄), and evaporated to a white solid,2.73 g. This material was absorbed onto 7 g of silica gel by dissolutionin the minimum quantity of a chloroform: methanol mixture (5:1, v/v),addition of the silica gel, and evaporation of the solvents. This silicagel was added as a suspension in ether to a silica gel column (25 g) andeluted with ether containing an increasing proportion of ethanol(2→10%). A proportion of the least polar amide diastereoisomer waseluted first in a pure state, and was recrystallized from ethyl acetateto give colorless crystals of one isomer of the title compound, m.p.223°-225° C., 105 mg.

Analysis %:

Found: C, 52.8; H, 5.3; N, 18.7.

C₁₃ H₁₅ ClN₄ O₂ requires: C, 53.0; H, 5.1; N, 19.0.

The remainder of the product was eluted as a mixture containing both thediastereoisomer characterized above and its more polar diastereomer (1:4by NMR). Recrystallization from ethyl acetate gave colorless crystals,m.p. 186°-189° C., 404 mg.

Analysis %:

Found: C, 53.0; H, 5.1; N, 19.4.

C₁₃ H₁₅ ClN₄ O₂ requires: C, 53.0; H, 5.1; N, 19.0.

EXAMPLE 402-(2,4-Dichlorophenyl)-3-(N-methyl-carbamoyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol##STR58##

3-Carboxy-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol(330 mg) was added to dry dioxan (10 ml) followed by1-hydroxybenzotriazole hydrate ("HOBT") (203 mg) anddicyclohexylcarbodiimide ("DCCD") (618 mg). After stirring for 1 hour atroom temperature (20° C.), methylamine (278 mg of 33% [by volume]solution in ethanol) was added and stirring was continued overnight (20hours). The resulting precipitate of dicyclohexylurea was removed byfiltration. The filtrate was added to water (50 ml) and solid sodiumbicarbonate was added to pH 8.

The mixture was then extracted with ethyl acetate (3×50 ml) and thecombined organic extracts were washed with water, dried (MgSO₄) andevaporated. The residue was dissolved in a small volume of methylenechloride and chromatographed on a Merck "Kieselgel 60" (Trade Mark)silica flash column in ethyl ether. Elution with ether (100 ml) followedby 15% (by volume) ethanol in ether (300 ml) yielded, by collection ofappropriate fractions, the title compound, 29 mg. m.p. 242°-244° C.

Since the recovered dicyclohexylurea contained a further quantity of thetitle compound, this was dissolved in a small amount of methanol andabsorbed onto Merck's "Kieselgel 60" (Trade Mark) silica (3 g), and theresulting slurry was then loaded onto a 10 g flash column of thismaterial in ethyl ether. Elution with 10% (by volume) ethanol in ether,and collection of appropriate fractions followed by recrystallizationfrom isopropanol, yielded a further quantity of the title compound (81mg).

Analysis %:

Found: C, 48.9; H, 4.8; N, 16.2.

Calculated for C₁₄ H₁₆ Cl₂ N₄ O₂ : C, 49.0; H, 4.7; N, 16.3.

EXAMPLE 41 (A)2-(2,4-Dichlorophenyl)-3-ethoxycarbonyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol4-(2,4-dichlorophenyl)-3,3-dimethyl-4-(1H-1,2,4-triazol-1-ylmethyl)beta-propiolactone##STR59##

2-(1H-1,2,4-Triazol-1-yl)-2',4'-dichloroacetophenone (2.56 g) in drytetrahydrofuran (20 ml) and ethyl alpha-bromoisobutyrate (1.475 ml) indry ether (10 ml) were added simultaneously to granulated zinc (1.5 g)in toluene (10 ml) over 20 minutes. The reaction mixture was then heatedat 80° C. for 18 hours. The cooled reaction mixture was poured ontoice-cold sulfuric acid (0.2N, 125 ml) and extracted with ether (200 ml).The ether extract was washed with brine, dried (MgSO₄), and concentratedin vacuo. The residue was flash chromatographed on silica (120 g) andeluted with 80% ethyl acetate/20% hexane. The initial fractions yieldedthe title ester, which was crystallized from ethyl acetate/hexane, yieldof the pure product, 61 mg, m.p. 95°-96° C.

Analysis %:

Found: C, 51.7; H, 5.2; N, 11.1.

Calculated for C₁₆ H₁₉ Cl₂ N₃ O₃ : C, 51.6; H, 5.1; N, 11.3.

The later fractions on evaporation gave the title beta-lactone, whichwas recrystallized from ethyl acetate/hexane, yield of the pure product240 mg, m.p. 177°-178° C.

Analysis %:

Found: C, 51.8; H, 3.9; N, 12.8.

Calculated for C₁₄ H₁₃ Cl₂ N₃ O₂ : C, 51.5; H, 4.0; N, 12.9.

(B)3-Carbamoyl-2-(2,4-dichlorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol

To a solution of2-(2,4-dichlorophenyl)-3-ethoxy-carbonyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol(75 mg) in ethanol (5 ml), aqueous ammonia (sp. gr. 0.88, 12 ml) wasadded and the solution was left at room temperature (20° C.) for eightdays. The solvent was then evaporated in vacuo, the residue waspartitioned between methylene chloride and water, and the organicextracts were washed with brine and dried (MgSO₄). Removal of solventfollowed by flash chromatography on silica (30 g) and elution with amixture of methylene chloride/methanol/ammonia (93:7:1) gave the titlecompound, m.p. 162°-163° C. (34.5 mg).

Analysis %:

Found: C, 48.8; H, 4.7; N, 15.8.

Calculated for C₁₄ H₁₆ Cl₂ N₄ O₂ : C, 49.0; H, 4.7; N, 16.3.

1-Carbamoyl-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-olwas prepared similarly to parts (A) and (B) above from appropriatestarting materials, and was confirmed spectroscopically to be identicalto the product of Example 4.

(D)3-Carbamoyl-2-(2,4-dichlorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol[alternative method to (B) above]

A solution of4-(2,4-dichlorophenyl)-3,3-dimethyl-4-(1H-1,2,4-triazol-1-yl-methyl)-beta-propiolactone(70 mg) in ethanol (4 ml) was treated with 0.88 sp. gr. ammonia (6 ml)and left to stand at room temperature for five days. The reactionmixture was then evaporated in vacuo and extracted and chromatographedby the method described in part (B) above to yield the title compound,m.p. 162°-163° C., (41 mg).

Analysis %:

Found: C, 48.6; H, 4.7; N, 15.9.

Calculated for C₁₄ H₁₆ Cl₂ N₄ O₂ : C, 49.0; H, 4.7; N, 16.3.

EXAMPLE 422-(2,4-Dichlorophenyl)-3-methyl-3-(N-methyl-carbamoyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

A solution of4-(2,4-dichlorophenyl)-3,3-dimethyl-4-(1H-1,2,4-triazol-1-ylmethyl)-beta-propiolactone(200 mg) in ethanol (5 ml) was treated with a solution of 35% (byvolume) methylamine in ethanol (5 ml), and the resulting solution wasleft to stand overnight at room temperature (20° C.). After evaporatingresidual methylamine and ethanol, the residue was triturated with hexaneand the resulting solid was crystallized from ethyl acetate/hexane toyield the title compound, m.p. 145°-146° C., (120 mg).

Analysis %:

Found: C, 50.2; H, 5.0; N, 15.9.

Calculated for C₁₅ H₁₈ Cl₂ N₄ O₂ : C, 50.4; H, 5.0; N, 15.7.

EXAMPLE 43 (A)4-(2,4-Dichlorophenyl)-4-(1H-1,2,4-triazol-1-ylmethyl)-beta-propiolactone

3-Carboxy-2-(2,4-dichlorophenyl)-1-(1H-1,2,4triazol-1-yl)propan-2-ol(948 mg) was dissolved in dry dioxan (20 ml) and 1-hydroxybenzotriazolehydrate (0.61 g) followed by dicyclohexylcarbodiimide (1.85 g), was thenadded. The resulting mixture was stirred at room temperature (20° C.)for two hours, triethylamine (455 mg) was added and stirring wascontinued overnight (19 hours). The mixture was added to water (100 ml)and extracted with ethyl acetate (3×50 ml). The precipitate ofdicyclohexylurea was removed by filtration after the first extraction.The combined organic extracts were washed with water, dried (MgSO₄) andevaporated. The residue was dissolved in a small amount of methylenechloride and loaded onto a flash column of Merck's "Kieselgel 60" (TradeMark) silica (12 g, 230-400 mesh) in ethyl ether. Elution with ethylether (100 ml) and then with 5% (by volume) acetone in ether (300 ml)gave, after collection of appropriate fractions, the title compound, 600mg, m.p. 178°-180° C.

Analysis %:

Found: C, 48.1; H, 3.0; N, 14.0.

Calculated for C₁₂ H₉ Cl₂ N₃ O₂ : C, 48.4; H, 3.0; N, 14.1.

(B)1-(N-Methylcarbamoyl)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol##STR60##

This reaction was carried out by the method of Example 42 using thestarting materials specified in the reaction scheme to give the titlecompound, confirmed spectroscopically to be the desired product and tobe identical to the product of Example 5.

EXAMPLE 441-Carbamoyl-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

This reaction was carried out by the method of Example 41(D) using thebeta-propiolactone provided above to give the title compound, confirmedspectroscopically to be the desired product and to be identical to theproduct of Example 4.

EXAMPLE 451-Carbamoyl-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol##STR61##

Bis(trimethylsilyl)acetamide (BSA) (1.99 g) was stirred at -70° C. indry tetrahydrofuran (15 ml) while n-butyllithium in hexane (6.3 ml,1.55M) was added dropwise over ten minutes. The resulting solution wasstirred at -70° C. for 30 minutes, then a solution of2-(1H-1,2,4-triazol-1-yl)-2',4'-dichloroacetophenone (1.0 g) in drytetrahydrofuran (10 ml) was added dropwise over 10 minutes, and themixture was stirred for 11/2 hours at -70° C. The reaction mixture wasallowed to warm to room temperature, and water (5 ml) and hydrochloricacid (7 ml, 2N) were added. The mixture was adjusted to pH 8 by theaddition of solid sodium bicarbonate, and extracted with ethyl acetate(3×10 ml). The combined extracts were washed with saturated sodiumchloride solution (3×10 ml), dried (MgSO₄), and evaporated to a gum, 1.1g.

This gum was chromatographed on silica ("Kieselgel 60", Merck), elutingwith ether containing 5% by volume ethanol. After the elution ofunreacted ketone, the product was eluted. The product-containingfractions were combined and evaporated to give the pure title compound,(0.21 g), confirmed spectroscopically to be identical to the product ofExample 4.

EXAMPLE 461-Carbamoyl-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-olby acid hydrolysis of nitrile

1-Cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1.0g) was heated at 60° C. for 21/2 hours in sulfuric acid (10 ml, 80%w/w). The mixture was cooled to room temperature, carefully treated withwater (100 ml), and adjusted to pH 9 with solid sodium hydroxide. Theresulting solution was extracted with methylene chloride (3×50 ml), andthe combined extracts evaporated to a gum, which was chromatographed onsilica gel, eluting with methylene chloride containing 3% by volumemethanol, increasing to 6% methanol. The fractions which contained theproduct (as judged by thin-layer chromatography) were combined andevaporated to a white solid, 0.91 g. This was dissolved in a mixture ofacetone and methylene chloride at reflux and the product wasprecipitated by the addition of hexane to give fine crystals, m.p.144°-145.5° C., 0.61 g, confirmed spectroscopically to be identical withthe product of Example 4 after drying under vacuum for 7 hours at 80° C.

EXAMPLE 472-(2,4-Dichlorophenyl)-1-[N-(2-[methylsulphinyl]ethyl)carbamoyl]-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

2-(2,4-Dichlorophenyl)-1-[N-(2-[methylthio]ethyl)carbamoyl]-3-(1H-1,2,4-triazol-1-yl)propan-2-ol(0.8 g) and m-chloroperbenzoic acid (85%, 0.35 g, 1 equiv.) were stirredat room temperature in a mixture of isopropanol and methylene chloride(1:1, v/v, 40 ml) for two days. The solvents were then removed underreduced pressure, and the residue was chromatographed on silica (Merck,"Kieselgel 60 ", 25 g), eluting with a mixture of chloroform, methanoland ammonia (sp. gr. 0.880) (160:20:5, v/v). A portion of the isomerwhich was eluted first was obtained pure, 116 mg, m.p. 168°-170° C.

Analysis %:

Found: C, 44.1; H, 4.4; N, 13.5.

C₁₅ H₁₈ Cl₂ N₄ O₃ S requires: C, 44.4; H, 4.5; N, 13.8.

The bulk of the material eluted as a mixture containing bothdiastereoisomers (330 mg). This material was used in the preparation ofthe sulphone which follows.

EXAMPLE 482-(2,4-Dichlorophenyl)-1-[N-(2-methylsulphonyl]ethyl)carbamoyl]-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

The unseparated mixture of diastereoisomers from the previous Example(330 mg) and m-chloroperbenzoic acid (140 mg) were stirred together in amixture of isopropanol and methylene chloride (1:1, v/v, 20 ml) at 0° C.After one hour at 0° C., the reaction mixture was allowed to reach roomtemperature and was stirred overnight. The solvents were then removedunder reduced pressure, and the residue was dissolved in ethyl acetate(50 ml). The resulting solution was washed with saturated sodiumbicarbonate solution (2×20 ml), then with saturated sodium chloridesolution (2×20 ml), dried (MgSO₄), and evaporated to a gum which wastriturated with diisopropyl ether to give a white solid, 209 mg, m.p.123°-124° C.

Analysis %:

Found: C, 42.6; H, 4.3; N, 13.2.

C₁₅ H₁₈ Cl₂ N₄ O₄ S requires: C, 42.8; H, 4.3; N, 13.3.

EXAMPLE 491-Aziridinylcarbonyl-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol##STR62##

1(N-[2-Hydroxyethyl]carbamoyl)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol(1.0 g), triphenylphosphine (1.09 g) and diethyl azodicarboxylate (0.72g) were stirred at room temperature for 20 hours in dry tetrahydrofuran(20 ml). The reaction mixture was then diluted with water (70 ml) andextracted with ethyl acetate (3×5 ml). The combined organic extractswere washed with saturated sodium chloride solution (2×20 ml), dried(MgSO₄), and evaporated to a brown gum. This material waschromatographed on Merck "Kieselgel 60" silica, eluting with 5% byvolume ethanol in ether increasing to 10% ethanol in ether. The elutedmaterial, which was one compound as judged by thin-layer chromatography,was crystallized from ethyl acetate/n-pentane to give colorless crystalsof the title compound, 441 mg, m.p. 151°-153° C.

Analysis %:

Found: C, 49.2; H, 4.0; N, 16.3.

C₁₄ H₁₄ Cl₂ N₄ O₂ requires: C, 49.3; H, 4.1; N, 16.4.

EXAMPLE 502-(2,4-Dichlorophenyl)-1-thiocarbamoyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

A mixture of1-cyano-2-(2.,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol(250 mg), 0,0-diethyl dithiophosphoric acid (0.5 ml) and water (0.1 ml)was heated on steam bath for three hours, evaporated under reducedpressure to an oil, and chromatographed on "Merck 60H" Trademark) silica(10 g) eluting with ethyl acetate. The eluted product, afterevaporation, was triturated under petroleum ether (b.p. 40°-60° C.) togive the title compound as a yellow solid (143 mg), m.p 158°-159° C.

Analysis %:

Found: C, 43.8; H, 3.6; N, 16.9.

Calculated for C₁₂ H₁₂ Cl₂ N₄ OS: C, 43.6; H, 3.6; N, 16.9.

EXAMPLE 51

The following illustrate pharmaceutical compositions for the treatmentof fungal infections:

(a) Capsule: 71 parts by weight of the compound of Example 1 or 2 aregranulated with 3 parts maize starch and 22 parts lactose and then afurther 3 parts maize starch and 1 part magnesium stearate are added.The mixture is regranulated and filled into hard gelatin capsules.

(b) Cream: 2 parts by weight of the compound of Example 3 are dissolvedin 10 parts of propylene glycol and mixed into 88 parts of a vanishingcream base.

(c) Pessary 2 parts by weight of the compound of Example 5 are suspendedin 98 parts of a warm liquified suppository base which is poured intomolds and allowed to solidify.

EXAMPLE 52

By employing the appropriate2-R-substituted-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane in the procedureof Example 1 or the appropriate ketone in the procedure of Example 2 thefollowing nitriles are obtained.

    ______________________________________                                         ##STR63##                                                                    R                  R                                                          ______________________________________                                        4-FC.sub.6 H.sub.4 3-FC.sub.6 H.sub.4                                         4-ClC.sub.6 H.sub.4                                                                              3-IC.sub.6 H.sub.4                                         4-BrC.sub.6 H.sub.4                                                                              3-Br-5-IC.sub.6 H.sub.3                                    4-IC.sub.6 H.sub.4 2-Cl-4-CF.sub.3 C.sub.6 H.sub.3                            4-CF.sub.3 C.sub.6 H.sub.4                                                                       2,4-(CF.sub.3).sub.2 C.sub.6 H.sub.3                       2-ClC.sub.6 H.sub.4                                                                              2,4-Br.sub.2 C.sub.6 H.sub.3                               2-BrC.sub.6 H.sub.4                                                                              2,5-Cl.sub.2 C.sub.6 H.sub.3                               2,5-F.sub.2 C.sub.6 H.sub.3                                                                      5-chloro-2-pyridyl                                         2-F-4-ClC.sub.6 H.sub.3                                                                          4-CH.sub.3 C.sub.6 H.sub.4                                 2-Cl-4-FC.sub.6 H.sub.3                                                                          4-(CH.sub.3).sub.2 CHC.sub.6 H.sub.4                       2,4,6-F.sub.3 C.sub.6 H.sub.2                                                                    4-(CH.sub.3).sub.3 CC.sub.6 H.sub.4                        4-Br-2,5-F.sub.2 C.sub.6 H.sub.2                                                                 4- -n-C.sub.4 H.sub.9 C.sub.6 H.sub.4                      2-Cl-4-CH.sub.3 C.sub.6 H.sub.3                                                                  2-Cl-4-CH.sub.3 OC.sub.6 H.sub.3                           4-CH.sub.3 OC.sub.6 H.sub.4                                                                      4- -n-C.sub.4 H.sub.9 OC.sub. 6 H.sub.4                    4-Cl-2-CH.sub.3 OC.sub.6 H.sub.3                                                                 2-Cl-4- -n-C.sub.3 H.sub.7 OC.sub.6 H.sub.3                ______________________________________                                    

EXAMPLE 53

The nitriles provided in the previous Example are converted to imidoether hydrochlorides by the method described in Preparation A and thisintermediate is converted to an amide of the formula below by the methodof Example 4. ##STR64## where R is as defined in the previous Example.

EXAMPLE 54

Employing the nitrile provided in Example 3 as starting material in thehydrolysis procedure of Example 6, Part A, provided1-carboxy-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol,m.p. 185°-187° C.

Analysis %:

Found: C, 50.8; H, 3.9; N, 14.8 4.

Calculated for C₁₂ H₁₁ F₂ N₃ O₃ : C, 50,0; H, 3.9; N, 14.8.

The remaining nitriles provided in Example 52 are converted to thecorresponding carboxylic acid of the formula below in like manner.##STR65##

EXAMPLE 55

The above carboxylic acids are reacted with the appropriate amine offormula HNR² R³ by the procedure of Example 6, Part B, to provide theamides of the formula below.

    ______________________________________                                         ##STR66##                                                                

    ______________________________________                                        R            R.sup.2      R.sup.3                                             ______________________________________                                        4-FC.sub.6 H.sub.4                                                                         H            C.sub.2 H.sub.5                                     4-ClC.sub.6 H.sub.4                                                                        CH.sub.3     C.sub.2 H.sub.5                                     4-BrC.sub.6 H.sub.4                                                                        H            (CH.sub.2).sub.5 CH.sub.3                           4-IC.sub.6 H.sub.4                                                                         C.sub.2 H.sub.5                                                                            C.sub.2 H.sub.5                                     4-CF.sub.3 C.sub.6 H.sub.4                                                                 (CH.sub.2).sub.3 CH.sub.3                                                                  (CH.sub.2).sub.3 CH.sub.3                           2-ClC.sub.6 H.sub.4                                                                        (CH.sub.2).sub.3 CH(CH.sub.3).sub.2                                                        (CH.sub.2).sub.3 CH(CH.sub.3).sub.2                 2-BrC.sub.6 H.sub.4                                                                        CH.sub.3     C.sub.6 H.sub.5 CH.sub.2                            2,5-F.sub.2 C.sub.6 H.sub.3                                                                (CH.sub.2).sub.3 CH.sub.3                                                                  4-CH.sub.3 C.sub.6 H.sub.4 CH.sub.2                 2-F-4-ClC.sub.6 H.sub.3                                                                    H            4-t-C.sub.4 H.sub.9 C.sub.6 H.sub.4 CH.sub.2                                  CH.sub.2                                            2-Cl-4-FC.sub.6 H.sub.3                                                                    CH.sub.3     4-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                2,4,6-F.sub.3 C.sub.6 H.sub.2                                                              (CH.sub. 2).sub.5 CH.sub.3                                                                 4-i-C.sub.4 H.sub.9 OC.sub.6 H.sub.4 CH.sub.2       4-Br-2,5-F.sub.2 C.sub.6 H.sub.2                                                           CH.sub.3     3-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2               2-Cl-4-CH.sub.3 C.sub.6 H.sub.3                                                            H            3-CF.sub.3 C.sub.6 H.sub.4                          4-CH.sub.3 OC.sub.6 H.sub.4                                                                C.sub.2 H.sub.5                                                                            2,4-Br.sub.2 C.sub.6 H.sub.3                        4-Cl-2-CH.sub.3 OC.sub.6 H.sub.3                                                           H            3,5-I.sub.2 C.sub.6 H.sub.3 CH.sub.2                3-FC.sub.6 H.sub.4                                                                         H            CH.sub.2 CF.sub.3                                   3-IC.sub.6 H.sub.4                                                                         H            1-adamantyl                                         3-BrC.sub.6 H.sub.4                                                                        H            2-adamantyl                                         3-Br-5-IC.sub.6 H.sub.3                                                                    C.sub.2 H.sub.5                                                                            2-pyridylmethyl                                     2-Cl-4-CF.sub.3 C.sub.6 H.sub.3                                                            H            3-pyridylmethyl                                     2,4(CF.sub.3).sub.2 C.sub.6 H.sub.3                                                        H            cyclopentyl                                         2,4-Br.sub.2 C.sub.6 H.sub.3                                                               H            cyclopropyl                                         2,4-Cl.sub.2 C.sub.6 H.sub.3                                                               CH.sub.3     cyclohexyl                                          2,4-Cl.sub.2 C.sub.6 H.sub.3                                                               H            cyclobutyl                                          2,5-Cl.sub.2 C.sub.6 H.sub.3                                                               CH.sub.3     cycloheptyl                                         5-chloro-2-pyridyl                                                                         H            4-pyridylmethyl                                     5-chloro-2-pyridyl                                                                         CH.sub.3     CH.sub.3                                            5-chloro-2-pyridyl                                                                         H            C.sub.2 H.sub.5                                     5-chloro-2-pyridyl                                                                         H            cyclopentyl                                         5-chloro-2-pyridyl                                                                         H            CH.sub.2 CONH.sub.2                                 4-CH.sub.3 C.sub.6 H.sub.4                                                                 CH.sub.3     CH.sub.3 CH.sub.2 CHCHCH.sub.2                      4-(CH.sub.3).sub.2 CHC.sub. 6 H.sub.4                                                      H            CH.sub.3 CHCHCH.sub.2                               4-(CH.sub.3).sub.2 CC.sub.6 H.sub.4                                                        C.sub.2 H.sub.5                                                                            CH.sub.2CHCH.sub.2                                  4-n-C.sub.4 H.sub.9 C.sub.6 H.sub.4                                                        CH.sub.3     CH.sub.2 CH.sub.2 OH                                2-Cl-4-CH.sub.3 OC.sub.6 H.sub.3                                                           H            (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                 4-n-C.sub.4 H.sub.9 OC.sub.6 H.sub.4                                                       H            CH.sub.3 SCH.sub.2 CH.sub.2                         2-Cl-4-n-C.sub.3 H.sub.7 OC.sub.6 H.sub.3                                                  CH.sub.3                                                                                    ##STR67##                                          2,4-Cl.sub.2 C.sub.6 H.sub.3                                                               H            CH.sub.3 S(O.sub.2)CH.sub.2 CH.sub.2                2,4-Cl.sub.2 C.sub.6 H.sub.3                                                               C.sub.2 H.sub.5                                                                            C.sub.6 H.sub.5 OCH.sub.2 CH.sub.2                  2,4-Cl.sub.2 C.sub.6 H.sub.3                                                               H            2,4-Cl.sub.2 C.sub.6 H.sub.3 OCH.sub.2 CH.sub.2                               2                                                   2,4-Cl.sub.2 C.sub.6 H.sub.3                                                               H            2,4-F.sub.2 C.sub.6 H.sub.3 OCH.sub.2 CH.sub.2      2,4-Cl.sub.2 C.sub.6 H.sub.3                                                               H            2,4-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2               ______________________________________                                        R             R.sup.2 R.sup.3                                                 ______________________________________                                        4-BrC.sub.6 H.sub.4                                                                          ##STR68##                                                      4-ClC.sub.6 H.sub.4                                                                          ##STR69##                                                      4-IC.sub.6 H.sub.4                                                                           ##STR70##                                                      4-ClC.sub.6 H.sub.4                                                                          ##STR71##                                                      2,4-Cl.sub.2 C.sub.6 H.sub.3                                                                 ##STR72##                                                      2,4-F.sub.2 C.sub.6 H.sub.3                                                                  ##STR73##                                                      2,4-F.sub.2 C.sub.6 H.sub.3                                                                  ##STR74##                                                      2,4-Cl.sub.2 C.sub.6 H.sub.3                                                                 ##STR75##                                                      2-ClC.sub.6 H.sub.4                                                                          ##STR76##                                                      4-ClC.sub.6 H.sub.4                                                                          ##STR77##                                                      3-FC.sub.6 H.sub.4                                                                           ##STR78##                                                      ______________________________________                                    

EXAMPLE 56

By employing the appropriate starting carboxylic acid or beta-lactoneand amine of formula R² R³ NH in place of methylamine in the proceduresof Examples 40 and 42, the corresponding amides of the formula below aresimilarly obtained. ##STR79## where R⁵ is H or methyl and R, R² and R³have the values shown in Example 55.

PREPARATION A3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H,1,2,4-triazol-1-yl)butyrimidicacid, ethyl ester dihydrochloride

1-Cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1g) was dissolved in dry ethyl alcohol (100 ml) and dry hydrogen chloridegas was bubbled in, at 0° C., for 10 minutes. The reaction mixture wasthen stirred at room temperature overnight, and then the solvent wasdecanted from the solid. The solid was then washed with dry ether anddried to yield the title compound, (1.15 g), m.p. 154°-156° C. Theproduct was used in Example 4.

Analysis %:

Found: C, 40.6; H, 4.4; N, 13.6.

Calculated for C₁₄ H₁₆ Cl₂ N₄ O₂.2HCl:

C, 40.4; H, 4.4; N, 13.5.

PREPARATION B

(i) 2-(1H-1,2,4-Triazol-1-yl)-2',4'-dichloro acetophenone (Y)

This compound was prepared similarly to the method described in BritishPatent Specification No. 1,512,918: ##STR80##

(ii) 2-(2,4-Dichlorophenyl)-2-(1H-1,2,4- triazol-1ylmethyl)oxirane (Z)##STR81##

In 20 ml of dry ethyl ether, 3.78 g (0.079 mole) of sodium hydride (50%dispersion in oil) was suspended with stirring. The ether was thenremoved by decantation, and the sodium hydride was dried in a stream ofdry nitrogen. Dry dimethyl sulphoxide (100 ml) was added followed by17.34 g (0.079 mole) of dry powdered trimethylsulphonium iodide, inportions, over 15 minutes. The resulting mixture was stirred for 30minutes at room temperature (20° C.). 18.33 g (0.072 mole) of compound(Y) as a solution in 50 ml of dry dimethyl sulphoxide was then added.The mixture was heated at 60° C. for three hours and then stood at roomtemperature overnight. The reaction mixture was cooled and quenched inice. The product was then extracted with ethyl acetate (600 ml). Theethyl acetate layer was separated, dried over magnesium sulphate, andconcentrated to give a red gum. Column chromatography of the gum onsilica, eluting with ethyl ether, gave the product (Z). On evaporation,6.62 g (34.4%) of the title product (Z) was obtained as a gum whichsolidified on trituration. The pure product melted at 57°-59° C.

Analysis %:

Found: C, 48.6; H, 3.3; N, 15.3.

Calculated for C₁₁ H₉ Cl₂ N₃ O: C, 49.0; H, 3.4; N, 15.5.

PREPARATION C (i) 2-Chloro-2',4'-difluoroacetophenone

Chloroacetyl chloride (113 g, 1.0 mole) was added dropwise to a stirredmixture of 1,3-difluorobenzene (114 g, 1.0 mole) and anhydrous aluminumchloride (146.6 g, 1.1 mole) at room temperature (20° C.). The mixturewas stirred for a further five hours at 50°-55° C. Methylene chloride(48.5 ml) was added slowly as the mixture was allowed to cool to roomtemperature. The methylene chloride layer was separated, washed withwater (2×320 ml) and the solvent removed by distillation at reducedpressure leaving a pale yellow solid (180 g).

A portion of the crude product (145 g) was crystallized from n-hexane(435 ml) giving the title compound (113 g, 73%) m.p. 47°-49° C.(literature* 46.5° C.) IR (KBr) and NMR (CDCl₃) were consistent with thedesired structure.

(ii) 2',4'-Difluoro-2-(1H-1,2,4-triazol-1-yl)-acetophenone hydrochloride##STR82##

To a mixture of 1,2,4-triazole (30.4 g, 0.44 mole) and triethylamine(15.1 g, 0.15 mole) in refluxing ethyl acetate (186 ml) was added asolution of 2-chloro-2',4'-difluoroacetophenone (38.1 g, 0.2 mole) inethyl acetate (80 ml). The mixture was refluxed for six hours thencooled to room temperature and the insolubles were removed byfiltration. the filtrate was washed with water (2×200 ml) and then thesolvent was removed by distillation at reduced pressure. The crudeproduct was dissolved in ethyl acetate (150 ml) then 25% w/v HCl gas inisopropanol was added. The mixture was granulated at 0° C. for one hourand then the solid was collected by filtration and dried to give thetitle compound (21.6 g, 40%), melting point 167°-170° C. IR (KBr) andNMR (DMSO) were consistent with the desired structure.

This intermediate was characterized as the free base, which was preparedby the following technique:

To a stirred slurry of sodium bicarbonate (16..8 g, 0.2 mole) and1,2,4-triazole (27.6 g, 0.4 mole) in refluxing toluene (180 ml) wasadded a solution of 2-chloro-2',4'-difluoroacetophenone (38.1 g, 0.2mole) in toluene (45 ml). The mixture was stirred at reflux for threehours and the water formed during the reaction was removed using a Deanand Stark trap. The reaction mixture was cooled to room temperature andthen water (180 ml) was added. The toluene layer was separated and thesolvent removed by distillation at reduced pressure. The resulting palebrown solid was crystallized from 1:1 ethyl acetate:n-hexane (70 ml)giving the title compound (3.9 g), melting point 103°-105° C. The IR(KBr) and NMR (CDCl₃) were consistent with the desired structure.

Analysis %:

Found: C, 53.6; H, 3.15; N, 18.7.

Calculated for C₁₀ H₇ F₂ N₃ O: C, 53.8; H, 3.2; N, 18.8.

For 4'-chloro-2-(1H-1,2,4-triazol-1-yl)acetophenone see German PatentApplication No. 2,431,407.

What is claimed is:
 1. A compound of the formula ##STR83## or apharmaceutically acceptable acid addition salt thereof, whereinR is2,4-dichlorophenyl, 2,4-difluorophenyl or 4-chlorophenyl; R¹ is --CONR²R³ where either (a) R² is H or C₁ -C₄ alkyl, and R³ is H, C₁ -C₄ alkyl,--CH₂ CF₃, carbamoylmethyl, allyl, 2-(methylthio)ethyl,2-(methylsulfinyl)ethyl, 2-(methylsulfonyl)ethyl, 4-chlorophenylmethylor 4-chlorophenylethyl; and R⁵ and R⁶ are each H or CH₃.
 2. A compoundas claimed in claim 1 wherein R is 2,4-dichlorophenyl or2,4-difluorophenyl.
 3. A compound as claimed in claim 1 wherein R¹ is--CONR² R³ wherein R² is H, CH₃ or C₂ H₅, and R³ is H, C₁ -C₄ alkyl,4-chlorophenylmethyl, 4-chlorophenylethyl, --CH₂ CF₃, carbamoylmethyl,allyl, 2-(methylthio)ethyl, 2-(methylsulfinyl)ethyl, or2-(methylsulfonyl)ethyl.
 4. A compound as claimed in claim 3 of theformula ##STR84##
 5. A compound as claimed in claim 4 wherein R is2,4-dichlorophenyl and R¹ is CONR² R³ where R² is H and R³ is H, C₁ -C₃alkyl, 4-chlorophenylmethyl, carbamoylmethyl, 2-(methylthio)ethyl, or2-(methylsulfonyl)ethyl.
 6. The compound as claimed in claim 5 whereinR₁ is CONH₂.
 7. The compound as claimed in claim 5 wherein R¹ isCONHCH₃.
 8. The compound as claimed in claim 5 wherein R¹ is CONHC₂ H₅.9. The compound as claimed in claim 4 wherein R is 2,4-difluorophenyland R¹ is CONHCH₃.
 10. A compound as claimed in claim 1 of the formula##STR85## wherein R¹ is CONH₂ or CONHCH₃.
 11. A compound as claimed inclaim 10 wherein R⁵ is H and R is 2,4-dichlorophenyl.
 12. The compoundas claimed in claim 11 wherein R¹ is CONHCH₃.
 13. A compound of theformula ##STR86## or a pharmaceutically acceptable acid addition saltthereof, wherein R is 2,4-dichlorophenyl and R¹ is CONH₂, CON(CH₃)₂ orCON(C₂ H₅)₂.